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Identification and Optimization of a Ligand-Efficient Benzoazepinone Bromodomain and Extra Terminal (BET) Family Acetyl-Lysine Mimetic into the Oral Candidate Quality Molecule I-BET432
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-15 , DOI: 10.1021/acs.jmedchem.2c01102 Philip G Humphreys 1 , Niall A Anderson 1 , Paul Bamborough 1 , Andrew Baxter 1 , Chun-Wa Chung 1 , Rosa Cookson 1 , Peter D Craggs 1 , Toryn Dalton 1 , Julie C L Fournier 1 , Laurie J Gordon 1 , Heather F Gray 1 , Matthew W Gray 1 , Richard Gregory 1 , David J Hirst 1 , Craig Jamieson 2 , Katherine L Jones 1 , Hripsimee Kessedjian 1 , David Lugo 1 , Grant McGonagle 1 , Vipulkumar K Patel 1 , Christopher Patten 1 , Darren L Poole 1 , Rab K Prinjha 1 , Cesar Ramirez-Molina 1 , Inmaculada Rioja 1 , Gail Seal 1 , Kayleigh A J Stafford 1 , Rishi R Shah 1 , Daniel Tape 1 , Natalie H Theodoulou 1 , Laura Tomlinson 1 , Sabri Ukuser 1 , Ian D Wall 1 , Natalie Wellaway 1 , Gemma White 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-15 , DOI: 10.1021/acs.jmedchem.2c01102 Philip G Humphreys 1 , Niall A Anderson 1 , Paul Bamborough 1 , Andrew Baxter 1 , Chun-Wa Chung 1 , Rosa Cookson 1 , Peter D Craggs 1 , Toryn Dalton 1 , Julie C L Fournier 1 , Laurie J Gordon 1 , Heather F Gray 1 , Matthew W Gray 1 , Richard Gregory 1 , David J Hirst 1 , Craig Jamieson 2 , Katherine L Jones 1 , Hripsimee Kessedjian 1 , David Lugo 1 , Grant McGonagle 1 , Vipulkumar K Patel 1 , Christopher Patten 1 , Darren L Poole 1 , Rab K Prinjha 1 , Cesar Ramirez-Molina 1 , Inmaculada Rioja 1 , Gail Seal 1 , Kayleigh A J Stafford 1 , Rishi R Shah 1 , Daniel Tape 1 , Natalie H Theodoulou 1 , Laura Tomlinson 1 , Sabri Ukuser 1 , Ian D Wall 1 , Natalie Wellaway 1 , Gemma White 1
Affiliation
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The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein–protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure–activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (41) as an oral candidate quality molecule.
中文翻译：
鉴定和优化配体高效的苯并氮杂酮溴结构域和额外末端 (BET) 家族乙酰赖氨酸模拟物进入口服候选质量分子 I-BET432
溴结构域和额外末端 (BET) 蛋白家族是人类表观基因组调控不可或缺的一部分，其失调与多种肿瘤学和炎症性疾病有关。破坏 BET 家族溴结构域乙酰赖氨酸 (KAc) 组蛋白-蛋白质与小分子 KAc 模拟物的相互作用已被证明是一种与疾病相关的作用机制，多种分子目前正在进行肿瘤学临床试验。这项工作描述了对已发表的 GSK pan-BET 溴结构域抑制剂的效率分析，这推动了一项战略选择，即专注于鉴定配体有效的 KAc 模拟物，假设亲脂效率可以在优化过程中得到显着提高。这种关注推动了配体高效且结构独特的苯并氮杂酮 KAc 模拟物的发现。41 ) 作为口服候选质量分子。
更新日期：2022-11-15
中文翻译：
鉴定和优化配体高效的苯并氮杂酮溴结构域和额外末端 (BET) 家族乙酰赖氨酸模拟物进入口服候选质量分子 I-BET432
溴结构域和额外末端 (BET) 蛋白家族是人类表观基因组调控不可或缺的一部分，其失调与多种肿瘤学和炎症性疾病有关。破坏 BET 家族溴结构域乙酰赖氨酸 (KAc) 组蛋白-蛋白质与小分子 KAc 模拟物的相互作用已被证明是一种与疾病相关的作用机制，多种分子目前正在进行肿瘤学临床试验。这项工作描述了对已发表的 GSK pan-BET 溴结构域抑制剂的效率分析，这推动了一项战略选择，即专注于鉴定配体有效的 KAc 模拟物，假设亲脂效率可以在优化过程中得到显着提高。这种关注推动了配体高效且结构独特的苯并氮杂酮 KAc 模拟物的发现。41 ) 作为口服候选质量分子。
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